Molecules Influencing Obesity: Leptin, Ghrelin, and Insulin

1. Obesity II Dr. Sumbul Fatma

2. Molecules that Influence Obesity The cause of obesity can be summarized by first law of thermodynamics: “Obesity results when energy intake exceeds energy expenditure” It involves a complex interaction of biochemical, neurologic, environmental, and psychologic factors

3. Hormonal control • Appetite is influenced by afferent, or incoming, signals—neural signals, circulating hormones, and metabolites—that impinge on the hypothalamus • These diverse signals prompt release of hypothalamic peptides, and activate outgoing, or efferent, neural signals • Adipocyte also functions as an endocrine cell that releases numerous regulatory molecules, such as leptin, adiponectin, and resistin • Adiponectin and resistin, may mediate insulin resistance observed in obesity.

4. Leptin • Studies of the molecular genetics of mouse obesity have led to the isolation of at least six genes associated with obesity • The most well-known mouse gene, ob, leads to severe hereditary obesity in mice • Gene's protein product is required to keep the animals' weight under control. The product of the ob gene is a hormone called leptin • Leptin is produced proportionally to the adipose mass and, thus, informs the brain of the fat store level • It is secreted by fat cells, and acts on the hypothalamus of the brain to regulate the amount of body fat through the control of appetite and energy expenditure. Leptin's secretion is suppressed by depletion of fat stores (starvation) and enhanced by expansion of fat stores (well-fed state). Daily injection of leptin causes overweight mice to lose weight and maintain weight loss. The protein also causes weight loss in mice that are not obese

5. Leptin Resistance • In humans, leptin increases the metabolic rate and decreases appetite • However, plasma leptin in obese humans is usually normal for their fat mass, suggesting that resistance to leptin, rather than its deficiency, occurs in human obesity • The receptor for leptin in the hypothalamus has been cloned and is produced by a gene known as db • In rodents, mutation in the db gene produces leptin resistance. However, the mutations thus far described in rodents do not appear to account for most human obesity • Therefore, current research is focused on other possible defects in leptin signal transduction in humans

6. Other Hormones Ghrelin- A peptide secreted primarily by the stomach • It is the only known appetite-stimulating hormone • Levels peak just before meals and drop afterward • Injection of ghrelin increases short-term food intake in rodents, and may decrease energy expenditure and fat catabolism Cholecystokinin - Peptides released from the gut following ingestion of a meal can act as satiety signals to the brain Insulin not only influences metabolism, but also promotes decreased energy intake

7. Bad News for Dieters • Leptin • Dieting decreases leptin levels • Reducing metabolism, stimulating appetite • Ghrelin • Levels in dieters are higher after weight loss • The body steps up ghrelin production in response to weight loss • The higher the weight loss, the higher the ghrelin levels

8. Metabolic Changes Observed in Obesity • The metabolic abnormalities of obesity reflect molecular signals originating from the increased mass of adipocytes • The predominant effects of obesity include dyslipidemias, glucose intolerance, and insulin resistance, expressed primarily in the liver, muscle, and adipose tissue

9. Metabolic syndrome • Abdominal obesity is associated with a threatening combination of metabolic abnormalities that includes glucose intolerance, insulin resistance, hyperinsulinemia, dyslipidemia (low high-density lipoprotein (HDL) and elevated VLDL), and hypertension • This clustering of metabolic abnormalities has been referred to as the metabolic syndrome, the insulin resistance syndrome, or syndrome X • Individuals with this syndrome have a significantly increased risk for developing diabetes mellitus and cardiovascular disorder • For example, men with the syndrome are three to four times more likely to die of cardiovascular disease.

10. Dyslipidemia • Insulin resistance in obese individuals leads to increased production of insulin in an effort by the body to maintain blood glucose levels • Insulin resistance in adipose tissue causes increased activity of hormone-sensitive lipase, resulting in increased levels of circulating fatty acids • These fatty acids are carried to the liver and converted to triacylglycerol and cholesterol • Excess triacylglycerol and cholesterol are released as VLDL, resulting in elevated serum triacylglycerols • Concomitantly, HDL levels are decreased.

11. Obesity and Health Obesity is correlated with an increased risk of death and is a risk factor for a number of chronic conditions, including • adult onset diabetes • Hypercholesterolemia • high plasma triacylglycerols • Hypertension • heart disease • some cancers • Gallstones • Arthritis • Gout • The relationship between obesity and associated morbidities is stronger among individuals younger than 55 years • After age 74, there is no longer an association between increased BMI and mortality.

12. Weight Loss • Weight loss in obese individuals leads to • decreased blood pressure • Decreased serum triacylglycerols • Low blood glucose levels • HDL levels increase • Mortality decreases (particularly deaths due to cancer) • Some obesity experts suggest that moderately overweight and otherwise healthy individuals should not obsess about weight loss, but rather should direct their energies to a healthier lifestyle, particularly including some exercise in their weekly routine.

13. Assessment • Is he overweight? Obese? • What are his key health issues?

14. Assessment • Assess the patient's readiness and willingness to lose weight: • Unfortunately those who are most concerned about their weights are not necessarily those who are at the highest health risk. • Those who are unable or unwilling to embark on a weight reduction program, but they are willing to take steps to avoid further weight gain or perhaps to work on other risk factors such as cigarette smoking, and they should be encouraged to do so. • For those not ready to act, the issue should be deferred and brought up at the next visit

15. Assessment • Measure BMI • Measure waist circumference • “Apple shape” body is higher risk for DM, CVD, HTN • Waist larger than 40 inches for men • Waist larger than 35 inches for women

16. Weight Reduction • The goals of weight management in the obese patient are • to induce a negative energy balance to reduce body weight • to maintain a lower body weight over the longer term.

17. Treatment Approach • A multi-faceted approach is best • Diet • Physical activity • Behavior change

18. Treatment Approach • Initial goal: 10% weight loss • Significantly decreases risk factors • Rate of weight loss • 1 to 2 pounds per week • Reduction of caloric intake 500-1000 per day • Slow weight loss is more stable • Rapid weight loss is almost always followed by weight gain

19. Treatment Approach • Aim for 4 - 6 months of weight loss effort • Most people will lose 20 to 25 pounds • After 6 months, weight loss is more difficult • Ghrelin & Leptin are at work! • Changes in resting metabolic rate • Energy requirements decrease as weight decreases • Diet adherence wavers • Set goals for weight maintenance for next 6 months, then reassess.

20. Behavioral Strategies • Keep a journal of diet & activity • Very powerful intervention! • Set specific goals: behaviors • Eating • Activity • Related behaviors • Track improvement • Weigh & measure on a regular basis

21. Physical activity • An increase in physical activity can create an energy deficit • Also, increases cardiorespiratory fitness and reduces the risk of cardiovascular disease, independent of weight loss • Persons who combine caloric restriction and exercise with behavioral treatment may expect to lose about 5–10% of preintervention body weight over a period of 4–6 months

22. Physical Activity • Physical activity should be an integral part of weight loss • Physical activity alone is less successful than a combined diet & exercise program • Increased activity alone does not decrease weight • Sustained activity does prevent weight regain • Reduces risk for heart disease & diabetes

23. Physical Activity • Start slowly • Many obese people live sedentary lives • Avoid injury • Early changes can be activities of daily living • Increase intensity & duration gradually • Long-term goal • 30 to 45 minutes or more of physical activity • 5 or more days per week • Burn 1000+ calories per week

24. Recommend Physical Activity • What does it take to burn 1000 calories per week? Gardening 5 hours Cycling 22 miles Running 11 miles Walking 12 miles Dancing 3 hours

25. Caloric restriction • Dieting is the most commonly practiced approach to weight control • Caloric restriction is ineffective over the long term for many individuals. More than 90% of people who attempt to lose weight regain the lost weight when dietary intervention is suspended • Nonetheless, it is important to recognize that, although few individuals will reach their ideal weight with treatment, weight losses of 10% of body weight over a 6-month period often reduce blood pressure and lipid levels, and enhance control of Type 2 diabetes • The health benefits of relatively small weight losses should, therefore, be emphasized to the patient • Weight loss on calorie-restricted diets is determined primarily by energy intake and not nutrient composition

26. Dietary Therapy • Weight reduction with dietary treatment is in order for virtually all patients with a BMI 25-30 who have comorbidities and for all patients over BMI 30. • Strategies of dietary therapy include teaching about calorie content of different foods, food composition (fats, carbohydrates, and proteins), reading nutrition labels, types of foods to buy, and how to prepare foods.

27. Low-Calorie Step I Diet • 1000 to 1200 kcal/day for women • 1200 to 1600 kcal/day for men • Adjust for current weight & activity • Too hungry? • increase kcal by 100 - 200/day • Not losing? • decrease kcal by 100 - 200/day

28. How Much is 1200 Calories? • Could you stick to 1200 per day? 1 Big Mac (580) 1 SMALL Fries (210) 1 SMALL shake (430)

29. Low-Calorie Step I Diet

30. Weight Maintenance: How Much Should People Eat? • Varies widely • Some averages, below

31. Pharmacologic treatment Two weight-loss medications are currently approved by the U.S. Food and Drug Administration for use in adults who have a BMI of 30 or higher Sibutramine,1 is an appetite suppressant that inhibits the reuptake of both serotonin and norepinephrine Orlistat,2 is a lipase inhibitor that inhibits gastric and pancreatic lipases, thus decreasing the breakdown of dietary fat into smaller molecules

32. Pharmacotherapy for Weight Loss • Adjunct to diet & physical activity • BMI ≥ 30 • Or, BMI ≥ 27 with other risk factors • Should not be used for cosmetic weight loss • Only for risk reduction • Use only when 6-month trial of diet & physical activity fails to achieve weight loss

33. Pharmacotherapy for Weight Loss • These drugs are only modestly effective • 2 to 10 kilogram loss • Most occurs in the first 6 months • If patient does not lose 2 kilograms in the first 4 weeks, success is unlikely • If the first 6 months is successful, continue medication as long as… • It is effective in maintaining weight, and • Adverse effects are not serious

34. Surgical Treatmant • Surgical procedures designed to reduce food consumption are an option for the severely obese patient who has not responded to other treatments • Surgery produces greater and more sustained weight loss than dietary or pharmacologic therapy, but has substantial risks for complications.

35. Weight Loss Surgery • Indications • 100 pounds overweight or more • Or, BMI > 40 • Or, BMI > 35 and 2 significant comorbidities • Age 18 to 60 • Documented failure at nonsurgical efforts • Psychological stability

36. Weight Loss Surgery • Complications of surgery • Mortality • <1% mortality in healthy young adults BMI < 50 • 2-4% mortality in patients with disease and BMI > 60 • Operative complications • < 10% • Late complications are uncommon • Incisional hernias • Gallstones • Vitamin B12 & iron deficiency • Weight loss failure • Neurologic symptoms in unusual cases

37. Summary